Synthetic peptides targeting a mast cell-specific G protein-coupled receptor MRGPRB2 display anti-infective potential

Antibiotics are urgently needed against drug-resistant bacterial infections. We report synthetic peptides with dual antimicrobial and immunomodulatory action. These peptides activate the human Mas-related G protein-coupled receptor-X2 (MRGPRX2) and its mouse ortholog, Mas-related G protein-coupled receptor-B2 (MRGPRB2), while directly killing bacteria. Unlike traditional MRGPRX2 agonists, these peptides contain protease-resistant d-amino acids, enhancing their stability. In a mouse infection model, the peptides demonstrated antimicrobial efficacy, and activated human MRGPRX2 but not its G165E missense variant. They also stimulated tumor necrosis factor alpha (TNF-α), C-C motif chemokine ligand 3 (CCL3), and interleukin-8 (IL-8) release in human mast cells via MRGPRX2 and triggered degranulation in mouse mast cells via MRGPRB2. The peptides increased vascular permeability, promoted neutrophil and monocyte recruitment, and cleared S. aureus infections in wild-type but not Mrgprb2 ^-/- mice. These findings suggest that synthetic peptides can target G protein-coupled receptors (GPCRs), leveraging mast cell immunomodulation to treat antibiotic-resistant infections. This study opens avenues for designing peptides and other molecules against infections by targeting GPCRs expressed in mast cells.